This invention relates to pharmaceutical compositions comprising magnesium compounds.
In man and in animals (see Williams RJP, Wacker WEC, Cation Balance in Biological Systems, J. Amer. Med. Ass. 1967; 201/1: 96-100) intracellular concentrations of the four principal cations, sodium, potassium, magnesium and calcium, are in equilibrium such that log concentration ratios of the divalent cations magnesium and calcium are directly related to those for the monovalent cations potassium and sodium: total intracellular concentrations of sodium plus potassium and of magnesium plus calcium are respectively similar to those in extracellular fluid, and thus are similar on both sides of the cell membrane.
In man and in animals (Bloch M., Magnesium Depletion: Possible Significance in Ischaemic Heart Disease, Brit. J. Hosp. Med. 1973; 91-98) magnesium depletion results in negative magnesium and potassium balance, and positive sodium, calcium, and water balance; in intracellular loss of magnesium and potassium, and gain in sodium and calcium; in increase in extracellular fluid space; and in hypomagnesaemia, hypokalaemia, and hypocalcaemia. All these changes are reversible with
I have postulated that normal vascular muscle tone, a major determinant of normal blood pressure, is critically dependent on cation balance; that magnesium plays a signficiant role in blood pressure control; and that cation imbalance resulting from magnesium depletion, leading to relative and absolute increase in intracellular and total body calcium and sodium, and to decrease in intracellular and total body magnesium and potassium, would be expected to result in increase in vascular muscle tone and in blood pressure. In support of this hypothesis, it was noted also that magnesium depletion has been observed in association with increase in renal, cardiac, and skeletal-muscle calcification in animals, and that increase in myocardial calcium content has been reported in magnesium-deficient hearts of patients with ischaemic heart disease.
Further support for this hypothesis comes from recent observations in normal subjects and in patients with essential hypertension, linking increase in blood pressure to change in cation balance, these indicating variously
(see Editorial. Essential hypertension: another defect? Lancet 1980; i: 1227-29. PA0 Editorial. Cells, ions, and blood pressure. Lancet 1982; ii: 965-967. PA0 Lever AF, Beretta-Piccoli C, Brown JJ, Davies DL, Fraser R, Robertson JIS. Sodium and potassium in essential hypertension. Brit. Med. J. 1981; 283: 463-468) PA0 (see Holly JMP, Goodwin FJ, Evans SJW, VandenBurg MJ, Ledingham JM. Re-analysis of data in two Lancet papers on the effect of dietary sodium and potassium on blood pressure. Lancet 1981; ii: 1384-87. PA0 Khaw KT, Thom S. Randomised double-blind cross-over trial of potassium on blood pressure in normal subjects. Lancet 1982; ii: 1127-29. PA0 MacGregor GA, Smith SJ, Markandu ND, Banks RA, Sagnella GA. Moderate potassium supplementation in essential hypertension. Lancet 1982; ii: 567-570.).
that blood pressure correlates positively with intracellular and total-body sodium content, and negatively with total-body potassium, plasma potassium concentration, and cellular efflux-rate of sodium; and that increase in blood pressure can be produced by increase in dietary sodium, and decrease in blood pressure by increase in dietary potassium
In dogs given intravenous solutions producing hypokalaemia, hypomagnesaemia, and hypokalaemia, alone and in combination, mean systolic and diastolic blood pressure increased; local hypermagnesaemia is associated with decrease in resistance in forelimb, kidney, coronary, gastric, mesenteric and hepatic vascular beds in the dog and in the human forearm (see Emerson, TE, Scott JB, Haddy FJ., Effects of acute multiple changes in plasma electrolyte levels on dog blood pressure., Am. J. Physiol. 1970; 218/1: 234-240). In cats treated intravenously with magnesium, resultant fall in heart rate and in diastolic and systolic blood pressure were dose-dependent and correlated negatively with plasma magnesium concentration (see Ebel H, Classen HG, Marquardt P, Spaeth M., Zur Pharmakologie und Pharmakokinetik von Magnesium, Muench. Med. Wochenschr. 1975; 117/29-30: 1243-48). It is argued in the Editorial in Lancet 1982; ii: 965-967, cited above, that increase in vascular muscle tone might result from increase in free intracellular calcium; that abnormality of sodium transport does not have a primary role in genesis of essential hypertension; and that cation changes observed in essential hypertension reflect an unidentified underlying abnormality, the so-called "innocent bystander".
These changes can all be produced by withdrawing dietary magnesium and reversed by magnesium repletion, and are compatible with the view that the reported abnormalities of sodium transport do not have a primary role in genesis of raised blood pressure in essential hypertension.
Since magnesium depletion might be widespread in Westernised communities (see Bloch M. Brit. J. Hosp. Med. 1973; 91-98 cited above), this might constitute a significant factor in the genesis of essential hypertension, and therefore treatment with magnesium might contribute to control of blood pressure in patients with this condition.
It is known that, when certain pharmaceutical compositions, in particular certain diuretics, are used, they cause loss of magnesium and potassium from the body. Toxicity of other pharmaceutical compositions, in particular of cardiac glycosides, is increased by potassium and magnesium depletion. Diuretics and cardiac glycosides are frequently prescribed for the same patient, and it is a known practice to administer also a potassium salt, e.g., potassium chloride, which might be given in a slow release preparation.
However, administration of potassium might give rise to unwanted side effects, e.g., vasoconstriction and gastric ulceration.
In particular, experimentally, these side effects can be prevented by magnesium ions, which have vasodilator activity, provided concentration of magnesium ions (m.eq./1.) exceeds that of potassium ions. Hence it has been proposed in U.K. Patent Specification No.1422193 and in U.S. Pat. No. 4,104,370 to provide a pharmaceutical composition comprising magnesium oxide, magnesium hydroxide, or a non-toxic pharmaceutically acceptable salt of magnesium in combination with a non-toxic pharmaceutically acceptable salt of potassium, the equivalent weight of magnesium being between 1 and 3, and preferably between 1 and 2 times the equivalent weight of the potassium, together with a pharmaceutical carrier, such that the rate of release of the magnesium and the rate of release of the potassium into the digestive system is controlled. Such a material may be co-prescribed or combined with a diuretic or cardiac glycoside.
Therapeutic usefulness of magnesium is limited by its action on the gut, causing purgation, unless administered in comparatively small doses. This limitation is overcome, in the use of the above-described composition, by the employment of a controlled-release preparation so that the magnesium is administered in therapeutically meaningful dosages.